The inside-out technique is safe and effective for thoracic central venous obstruction.

BACKGROUND: Thoracic central venous obstruction (TCVO) presents a challenging scenario for patients requiring central venous access. The inside-out technique for crossing occluded veins has been described; however, to date, case series have reported on a limited number of patients. The purpose of the present study was to evaluate the indications for, efficacy of, and outcomes with the inside-out technique at a single tertiary academic center, with close attention to the severity of TCVO using the Society of Interventional Radiology (SIR) TCVO classification. METHODS: Patients who had undergone central venous access using the inside-out technique were identified from August 2007 to May 2021. The patient demographics, procedure indication, procedural details, SIR TCVO classification, outcomes, and procedure-related complications were recorded. Statistical analysis was performed using analysis of variance. RESULTS: A total of 221 patients (109 men [49.3%] and 112 women [50.6%]) had undergone 338 inside-out procedures. Of the 221 patients, 49 had undergone the procedure multiple times (25 two times, 11 three times, 13 more than three times). The average patient age was 54.7 ± 14.8 years. The indications (n = 362) for the procedure included dialysis access (n = 230; 63.5%), infusion of parenteral nutrition, antibiotics, chemotherapy, or other medication (n = 81; 22.3%), cardiac access (n = 39; 10.8%), and other (n = 12; 3.3%); more than one indication for 20 procedures. Type 1 SIR TCVO was found during 147 procedures (43.5%), followed by type 4 for 142 (42.0%), type 2 for 36 (10.7%), type 3 for 6 (1.8%), and unable to determine for 7 (2.0%). The access site was the right femoral vein for 322 procedures (95.3%), left femoral vein for 14 (4.1%), and transhepatically for 2 (0.6%). The exit site location was the right supraclavicular region for 274 (81.3%), right subclavicular for 52 (15.4%), left supraclavicular for 3 (0.9%), left subclavicular for 6 (1.8%), and not defined for 2 (0.6%). Types 3 and 4 were associated with longer fluoroscopy times and more contrast compared with types 1 and 2. The median follow-up and device duration was 56.0 days and 76.5 days, respectively. No differences were found in device duration between the SIR TCVO types. Removal of a catheter was documented for 166 patients. The indications for removal included infectious causes (non-catheter-related bacteremia, catheter-related infection or bacteremia) for 70 (42.1%), catheter malfunction for 34 (20.5%), new hemodialysis access for 19 (11.5%), no longer needed for 19 (11.5%), patient removal of the catheter by 13 (7.8%), and replacement of a temporary catheter with a tunneled device for 11 (6.6%). No procedural complications were associated with the inside-out technique or catheter removal. CONCLUSIONS: For a variety of indications, we have shown that the inside-out technique is safe and effective for establishing central venous access in patients with TCVO and can be performed repeatedly. More complex obstructive patterns were associated with longer fluoroscopy times and greater contrast administration. Durability was primarily limited by infectious complications.

Contemporary Use of the Femoropopliteal Vein in Vascular Reconstructions.

INTRODUCTION: Current practice patterns favor endovascular treatment, resulting in fewer open procedures. When needed, greater saphenous vein and/or prosthetic conduits are considered the first choice for open vascular bypass. However, there is a cohort of patients in which these conduits are either not available or not suitable to address the surgical requirements. One alternative is to use femoropopliteal vein (FPV), an often-overlooked conduit. We report on the contemporary use of FPV in a tertiary vascular institution. METHODS: All patients who underwent FPV harvest, as defined by CPT code 35572, between 2005 and 2019 were identified. Patient demographics (sex, age, baseline laboratory values, medical co-morbidities), indication for use of FPV, complications specific to vein harvest, operative details, post-operative course, and outcomes were recorded. RESULTS: Ninety patients had harvest of FPV for creation of 123 conduits. In this study, a conduit was defined as a segment of vein used to perfuse a distinctly separate vascular bed. We identified four cohorts in which FPV was used: aorto-iliac reconstruction in 38 patients for infected graft (19), occlusive disease (8), aortitis (5), mycotic aneurysm (5), and malignancy (1); peripheral artery revascularization in 26 patients for ilio-femoral reconstruction (15), femoropopliteal reconstruction (4), upper extremity/cerebrovascular reconstruction (6), and coronary bypass (1); mesenteric revascularization in 20 patients for acute or acute on chronic ischemia (12), chronic ischemia (7) or aneurysm (1); and dialysis access in 6 patients. There was a high incidence of pre-existing comorbid conditions in all groups, but most notably those patients who underwent aorto-iliac reconstruction. Harvest-related or conduit-related complications included compartment syndrome, graft-associated hemorrhage, surgical site infection, and lymphatic complications. Primary graft patency at 3 years was 83% ± 4% (aorto-iliac), 83% ± 6% (peripheral), 100% (mesenteric), and 23% ± 19% (dialysis access, P < 0.001). CONCLUSIONS: While use of FPV has potential significant harvest-related, conduit-related, or systemic complications, FPV is useful for a variety of needs, almost universally available, and durable. In the current era where endovascular approach is the focus, FPV should not be forgotten as a potential conduit that can be used for a variety of vascular reconstruction indications.

Left innominate vein creation using left internal jugular vein tunneled to right internal jugular vein.

BACKGROUND: Left innominate vein occlusion is a known complication of pacemaker and central venous catheter placement. For dialysis-dependent patients with an arteriovenous fistula (AVF), this can prevent successful hemodialysis and may require surgical intervention. CASE REPORT: An 8-month-old male was diagnosed with hemolytic uremic syndrome and became dialysis-dependent at 11 months of age. After multiple vascular access and peritoneal dialysis complications, the patient had construction of a brachiobasalic AVF in his left arm at 13 years old. While waiting for the AVF to mature, an attempt to remove a previously placed left subclavian vein port-a-cath was unsuccessful and a follow-up imaging revealed that the vessel had become occluded. The fistula remained patent, but due to arm swelling and venous obstruction, his fistula was not accessible. Multiple attempts to percutaneously cross the left innominate vein were unsuccessful and the patient was referred for surgical intervention. At 15 years old, the patient was taken to the operating room for transposition of the left internal jugular vein (LIJ) to the right internal jugular vein (RIJ). The LIJ was transected under the mandible and anastomosed to the RIJ. Subsequently the patient underwent VWING insertion rather than venous transposition for constant site dialysis. Although he has required frequent transcatheter dilation of the LIJ-RIJ anastomosis, the patient was successfully dialyzed using this fistula for 5 years. The patient received a cadaveric renal transplant at 5 years 20 days. CONCLUSIONS: In cases of left innominate vein stenosis, transposing the LIJ can create a new left innominate vein that can alleviate venous hypertension and preserve fistula function. This procedure avoids sternotomy and only requires one anastomosis.

Direct Retrograde Bypass is Preferable to Antegrade Bypass for Open Mesenteric Revascularization.

BACKGROUND: Mesenteric bypass grafts can be constructed either antegrade or retrograde. There is debate regarding which is the optimal approach. We have modified the technique for retrograde mesenteric revascularization using a direct open retrograde revascularization (DORR) technique. This report is a retrospective single-institution study that describes the DORR technique and compares it with antegrade mesenteric bypass. METHODS: The medical records of patients undergoing open mesenteric bypass between January 2001 and December 2017 for mesenteric ischemia were reviewed. Patients who underwent mesenteric thromboembolectomy, retrograde stenting, or bypass for aneurysmal disease were excluded. Patient demographics, operative details, and follow-up data were recorded. Antegrade bypasses were constructed using a polyester, collagen-coated, knitted, (Maquet, Getinge Group)- bifurcated graft. The supraceliac aorta was exposed, and the Dacron graft limbs were tunneled to the celiac and/or superior mesenteric artery (SMA). The DORR was constructed by anastomosing a vein graft to an iliac artery. The vein was tunneled through the base of the small bowel mesentery to create a direct course to the SMA. When revascularization to both the SMA and celiac vessels was indicated, the vein was anastomosed to the SMA in a side-to-side fashion with the distal vein tunneled through the mesocolon and anastomosed in a end-to-side fashion to the hepatic artery. Statistical analysis was done using Student's t-test, Mann-Whitney U test, Fisher's exact test, and log-rank test with a P ≤ 0.05 considered significant. RESULTS: Forty-one patients underwent open mesenteric bypass: 16 antegrade and 25 retrograde. Patient age, gender, and body mass index were similar. Indication for operation was acute ischemia in a greater portion of patients undergoing retrograde bypass (P = 0.025). For antegrade bypasses, Dacron was used in 15 and saphenous vein in 1. The DORR bypass originated from an iliac artery (21), limb of an aortofemoral graft (2), or infrarenal aorta (2). All DORR were constructed using veins (19 femoral veins and 6 greater saphenous veins). In DORR configurations, the bypass was created to only the SMA in 23 cases (92%). By comparison, in antegrade bypasses, the bypass was constructed to both the SMA and celiac arteries in all but 1 case (P < 0.00001). Median operative time was significantly shorter for DORR compared with antegrade bypass (282 vs. 375 min; P < 0.05). Blood loss, need for second-look laparotomy, morbidity, mortality, length of stay, and discharge disposition were similar between groups. There was a shift in favor of the DORR technique in the second half of the study (4 of 15 [27%] DORR from 2001 to 2009 vs. 21 of 26 [81%] DORR from 2010 to 2017). In survivors, 57% of the antegrade cohort and 74% of the DORR cohort had documented follow-up (average, 47.5 ± 59.9 and 28.8 ± 31.3 months, respectively). No difference was noted in survival between groups. All grafts in both cohorts were patented at follow-up. CONCLUSIONS: Direct tunneling of the graft under the mesentery with the DORR technique avoids concern for kinking and has shorter operative time despite the need for vein harvest. No differences were noted in long-term survival between patient groups. The use of a venous conduit makes DORR adaptable for both chronic and acute mesenteric ischemia. These factors have resulted in the DORR technique to be our preferred method for open mesenteric revascularization.

Treatment of postoperative high-volume lymphatic complications using isosulfan blue.

BACKGROUND: Lymphocele (LC) and lymphocutaneous fistula (LF) are infrequent but serious complications that occur when lymphatics are disrupted during a vascular procedure. Conservative management with bed rest, extremity elevation, aspiration, and pressure dressing is often ineffective. This study evaluated the effectiveness of isosulfan blue (ISB) to identify disrupted lymphatics for ligation. METHODS: Between 1998 and 2016, there were 33 lymphatic complications treated with ISB-directed ligation in 32 patients. The patients' records were retrospectively reviewed, recording demographics, comorbid conditions, index vascular operation causing the lymphatic complication, details of the procedure done to treat the lymphatic complication, and outcomes. In each patient, between 1 and 3 mL of ISB was injected in the subcutaneous tissue of the interdigital web space. The wound associated with the lymphatic complication was opened. The appearance of dye within the wound identified disrupted lymphatic ducts for suture ligation. RESULTS: The lymphatic complications were either LC (11 [33%]) or LF (22 [66%]) and were associated with femoral vein harvest (9), great saphenous vein harvest (8), exposure of femoral arteries (13), creation of an upper extremity fistula (1), repeated femoral access for coronary angiography, or excision of an LC (1). Most patients were male (66%), and the mean age was 56.8 ± 13.1 years. In comparing patients with LF and LC, the diagnosis of LF was made earlier (13.8 ± 7.0 days vs 23.4 ± 14.1 days; P = .02), and treatment occurred sooner for LF than for LC (22.1 ± 8.1 days vs 48.8 ± 51.2 days; P = .02). In all patients, ISB identified one or more disrupted lymphatics. The appearance of the ISB dye within the wound after injection was rapid, often within 5 to 10 minutes. After ligation of the lymphatics, most wounds were closed primarily (26 [79%]), but a muscle flap (5 [15%]), negative pressure dressing (1 [3%]), and dressing changes (1 [3%]) were also used. Wound healing was achieved in all patients on average 32.5 ± 21.5 days after lymphatic ligation. CONCLUSIONS: The current series is one of the largest reported experiences using ISB to identify injured lymphatics responsible for LC or LF. Lymphatic complications after a vascular procedure usually occur within 3 weeks of the index vascular procedure, with LF being identified and treated earlier than LC. ISB injection rapidly identifies disrupted extremity lymphatics. Ligation of these lymphatics results in reliable resolution of the lymphatic complication.

The Feasibility of Real-Time Intraoperative Performance Assessment With SIMPL (System for Improving and Measuring Procedural Learning): Early Experience From a Multi-institutional Trial.

PURPOSE: Intraoperative performance assessment of residents is of growing interest to trainees, faculty, and accreditors. Current approaches to collect such assessments are limited by low participation rates and long delays between procedure and evaluation. We deployed an innovative, smartphone-based tool, SIMPL (System for Improving and Measuring Procedural Learning), to make real-time intraoperative performance assessment feasible for every case in which surgical trainees participate, and hypothesized that SIMPL could be feasibly integrated into surgical training programs. METHODS: Between September 1, 2015 and February 29, 2016, 15 U.S. general surgery residency programs were enrolled in an institutional review board-approved trial. SIMPL was made available after 70% of faculty and residents completed a 1-hour training session. Descriptive and univariate statistics analyzed multiple dimensions of feasibility, including training rates, volume of assessments, response rates/times, and dictation rates. The 20 most active residents and attendings were evaluated in greater detail. RESULTS: A total of 90% of eligible users (1267/1412) completed training. Further, 13/15 programs began using SIMPL. Totally, 6024 assessments were completed by 254 categorical general surgery residents (n = 3555 assessments) and 259 attendings (n = 2469 assessments), and 3762 unique operations were assessed. There was significant heterogeneity in participation within and between programs. Mean percentage (range) of users who completed ≥1, 5, and 20 assessments were 62% (21%-96%), 34% (5%-75%), and 10% (0%-32%) across all programs, and 96%, 75%, and 32% in the most active program. Overall, response rate was 70%, dictation rate was 24%, and mean response time was 12 hours. Assessments increased from 357 (September 2015) to 1146 (February 2016). The 20 most active residents each received mean 46 assessments by 10 attendings for 20 different procedures. CONCLUSIONS: SIMPL can be feasibly integrated into surgical training programs to enhance the frequency and timeliness of intraoperative performance assessment. We believe SIMPL could help facilitate a national competency-based surgical training system, although local and systemic challenges still need to be addressed.

Impact of Residents on Surgical Outcomes in High-Complexity Procedures.

BACKGROUND: There are different views on the effects of resident involvement on surgical outcomes. We hypothesized that resident participation in surgical care does not appreciably alter outcomes. STUDY DESIGN: We analyzed an American College of Surgeons NSQIP subset of inpatients having procedures with high complexity, including 4 surgical specialties (general surgery, cardiothoracic surgery, neurosurgery, and vascular surgery) with the highest mean work relative value units. We evaluated surgical outcomes in patients having procedures performed by the attending surgeon alone, or by the attending surgeon with assistance from at least one surgical resident (PGY1 to PGY≥6). Outcomes measures included operative mortality, composite morbidity, and failure to rescue (FTR). Propensity-score matching minimized the effects of nonrandom assignment of residents to procedures. RESULTS: In 266,411 patients, unmatched comparisons showed significantly higher operative mortality and composite morbidity rates, but decreased FTR, in operations performed with resident involvement. After propensity-score matching, there were small but significant resident-related increases in composite morbidity, but significant improvement in FTR. Senior-level resident involvement translated into improved outcomes, especially in cardiothoracic surgery procedures where >63.6% of procedures had PGY≥6 resident involvement. Resident involvement attenuated the significant worsening of operative mortality and FTR associated with multiple serious complications in individual patients. Measures of resource use increased modestly with resident involvement. CONCLUSIONS: We found substantial improvement in FTR with resident involvement, both in unmatched and propensity-matched comparisons. Senior-level resident participation seemed to attenuate, and even improve, surgical outcomes, despite slightly increased resource use. These results provide some reassurance about teaching paradigms.

Debate: Whether an endovascular-first strategy is the optimal approach for treating acute mesenteric ischemia.

Acute mesenteric ischemia continues to be a life-threatening insult in often-elderly patients with many comorbidities. Recognition and correct diagnosis can be an issue leading to delays in therapy that result in loss of bowel or life, or both. The basic surgical principals in treating acute mesenteric ischemia have long been early recognition, resuscitation, urgent revascularization, resection of necrotic bowel, and reassessment with second-look laparotomies. Endovascular techniques now offer a less invasive alternative, but whether an endovascular-first or open surgery-first approach is preferred in most patients is unclear. Our discussants will attempt to clarify these issues.

A Regional Experience With Vascular Surgery Mock Oral Examinations.

INTRODUCTION: In 2006 the Southern Association for Vascular Surgery (SAVS) implemented a mock oral examination program to prepare trainees for the Vascular Surgery Certifying Examination (VCE). METHODS: Participating examinees and examiners were identified from SAVS Recorder records and contacted via e-mail with a request to participate in an anonymous online survey. Examinees were asked about passage on American Board of Surgery examinations and perceptions of the mock oral program. Examiners were asked for their perceptions of the examination, applicant performance, and perceived areas for training improvement. Board passage rates for the group and national comparison data were provided in a de-identified fashion by American Board of Surgery. RESULTS: From 2006 to 2014, 158 examinees and 86 examiners participated in the SAVS mock orals program. In all, 33% of examinees and 35% of examiners completed the anonymous survey. Of the examinees, 27 (60%) reported passage of the mock oral examination on their first attempt and 7 of 9 (78%) reported passage on the second attempt. Second year in training was significantly associated with passage of the mock oral (p = 0.002). Of the examinees questioned, 100% "would recommend" the SAVS mock oral examinations to future trainees. Of the responding examiners, 90% felt that the SAVS mock oral examinations were "comparable" to the VCE and 87% "strongly agreed" that the exercise was a valuable preparatory tool. Examiners identified "ability to describe technical aspects of open vascular techniques" and "management of complications associated with vascular disease processes and operations" as commonly displayed deficits among examinees (80% and 77%, respectively). In all, 115 examinee participants from the SAVS mock orals had taken the VCE between 2006 and 2014. Of them, 90 (78%) passed the VCE on their first attempt. During the same time interval, the national first-time pass rate for the VCE was 86%. CONCLUSIONS: Although participation in the SAVS mock orals was overwhelmingly assessed as a positive preparatory experience by examinees and examiners, no incremental advantage in VCE passage was observed. Explanations for the worse-than-average performance on the VCE are not clear but likely involve numerous factors, including participation bias. Importantly, examiners in the SAVS mock oral process felt that the exercise closely simulated the VCE and uniformly reported pervasive deficits in the areas of demonstrated understanding of open surgical techniques and management of complications. This investigation guides further examination of VCE simulation exercises to assist in guiding the use of educational resources at both institutional and professional society levels.

Abdominal compartment syndrome associated with endovascular and open repair of ruptured abdominal aortic aneurysms.

BACKGROUND: Abdominal compartment syndrome (ACS) is a known complication of ruptured abdominal aortic aneurysm (rAAA) repair and can occur with either endovascular (EVAR) or open repair. We hypothesize that the underlying mechanism for the development of ACS may differ for patients treated with EVAR or open operation. METHODS: All patients who presented with rAAA at a tertiary care medical center between January 2005 and December 2010 were included in the study. Demographic factors, type of repair (open vs EVAR), development of ACS, intraoperative and postoperative fluid requirements, estimated blood loss, length of stay, and morbidity and mortality were recorded. Student t-test and Fisher exact test were performed. A P value < .05 was considered significant. RESULTS: Seventy-three patients, 62 men and 11 women with an average age of 70.5 years, were treated for rAAA. Forty-four (60%) underwent open repair; 29 (40%) had EVAR. Overall mortality was 42% (31 of 73), with mortality being 31% (9 of 29) in EVAR and 48% (21 of 44) in open repair. ACS developed in 21 patients (29%), more frequently in open repair than in EVAR (15 of 44 [34%] vs 6 of 29 [21%]; P = NS). Mortality was higher in patients who developed ACS compared with those without ACS (13 of 21 [62%] vs 17 of 52 [33%]; P = .022). This finding was especially pronounced in the EVAR group, in which mortality in patients with ACS was 83% (5 of 6) compared with 17% (4 of 23) without ACS (P = .005). Intraoperative fluid requirements were significantly higher in EVAR patients who developed ACS compared with those without ACS, including packed red blood cells (5600 mL vs 1100 mL; P < .0001), total blood products (9300 mL vs 1500 mL; P < .001), crystalloid (11,200 mL vs 4500 mL; P < .001), and estimated blood loss (5000 mL vs 660 mL; P = .006). In patients treated with open repair, there were no significant differences in intraoperative fluid requirements between those who developed ACS and those without ACS. However, patients who developed ACS after open repair required significantly more crystalloid on the first and second postoperative days (first postoperative day, 8300 mL vs 5600 mL [P = .01]; second postoperative day, 6500 mL vs 3800 mL [P = .004]). CONCLUSIONS: This study demonstrates that the development of ACS after repair of rAAA is associated with increased mortality, especially in EVAR-treated patients. The higher intraoperative blood and blood product requirements associated with ACS in EVAR patients suggest that one potential cause of early ACS is continued hemorrhage from lumbar and inferior mesenteric vessels through the ruptured aneurysm sac. Hence, open ligation of such vessels should be considered in patients developing early ACS after EVAR for rAAA.

Diagnosis and treatment of arterial-ureteric fistula.

A 45-year-old woman presented with gross hematuria. She had previously undergone an aortobifemoral bypass that subsequently became infected. The infected graft was removed and replaced with homograft. An arterioureteric fistula was identified with angiography and the patient was treated with an iCast stent graft. Diagnosis of arterioureteric fistula should be suspected in patients with gross hematuria and associated risk factors. We would recommend angiography for diagnosis and simultaneous treatment with a stent graft, although the long-term durability and outcome is unknown.

Short-term outcomes for open revascularization of chronic mesenteric ischemia.

BACKGROUND: Surgical bypass as treatment for chronic mesenteric ischemia (CMI) is performed to alleviate symptoms of weight loss and postprandial pain and to prevent catastrophic intestinal necrosis. Among the studies that report outcomes for mesenteric bypass, few focus on the type of conduit. The purpose of this study was to evaluate contemporary short-term outcomes of patients who underwent aortomesenteric bypass for CMI, with specific attention given to the conduit used--prosthetic versus vein. METHODS: Data from the American College of Surgeons National Surgical Quality Improvement Program Participant Use File were analyzed for demographic and clinical risk variables, mortality, and 22 defined complications (morbidity) between 2005 and 2009 from more than 200 participating hospitals. The database was queried for patients undergoing aortomesenteric bypass with vein (Current Procedural Terminology [CPT] 35531) or nonvein (CPT 35631) whose preoperative diagnosis was CMI (International Classification of Diseases, 9th Revision code 557.1). Outcomes and risk variables were compared using univariate analysis and independent sample t tests for continuous variables. RESULTS: One hundred fifty-six patients underwent mesenteric revascularization--119 (76%) women and 37 (24%) men with an average age of 65 ± 13 years. The conduit used was vein in 44 (28%) and prosthetic graft in 112 (72%). There were no statistically significant differences between the two groups in mean age, smoking history, recent weight loss, obesity (body mass index: >25) rates, length of operation, reoperation frequency, and early graft failure. More patients undergoing bypass with vein had an associated bowel resection and preoperative sepsis or systemic inflammatory response syndrome. Additionally, patients with a vein graft had a higher percentage of a contaminated surgical site (30% vs. 7%, P = 0.001) and underwent emergent surgery more frequently (16% vs. 4%, P = 0.012). Mortality was higher in patients in whom a vein graft was used (16% vs. 5%, P = 0.039). There were no differences noted between the two groups in length of stay or postoperative complications, including infectious complications, renal insufficiency, myocardial infarction, and stroke. CONCLUSIONS: Thirty-day mortality was higher in patients who underwent mesenteric bypass with vein. However, this group also had a higher incidence of emergent surgery, bowel resection, and contaminated operative field. This suggests that vein grafts were preferentially used when bowel infarction was suspected. The higher mortality is likely due to patient factors, such as the extent of bowel ischemia at the time of operation, rather than the type of conduit used. If expeditious revascularization is done before development of bowel infarction, vein or prosthetic conduit would be expected to function equally well.

Thrombin injection for the treatment of mycotic gluteal aneurysm.

Gluteal aneurysms are rare entity, whose surgical or endovascular management is traditionally challenging. Infectious source being increasingly more common as the underlying etiology. We herein describe successful implementation of direct thrombin injection as another therapeutic option for these patients.

Spontaneous superior mesenteric artery dissection: report of 2 patients and review of management recommendations.

Spontaneous superior mesenteric artery dissection is rare and presents with variable symptomatology. Optimal treatment depends on the presentation; asymptomatic patients can be managed expectantly. Endoluminal intervention or open reconstruction is warranted in patients with persistent symptoms or intestinal ischemia. As more of these patients are identified with increasing utilization of computed tomography (CT), our understanding of the pathophysiology and best treatment will improve.